Improving tumor drug deposition by physical activation of liposomes and prodrugs

Abstract

Effective chemotherapy treatment of the primary tumor could be achieved by exposing this tumor to a high concentration of the drug for a long period of time. Since most drugs are systemically administrated and are not tumor specific, they cause unwanted toxicities in the normal tissue. Hence, there is a need for local drug delivery in the primary tumor. The goal of this thesis is to improve local drug deposition by physical activation of temperature sensitive liposomes (TSLs) and prodrugs. TSLs release their drug upon elevated temperatures, i.e. hyperthermia (41-43°C). The efficacy of TSLs was investigated I) in vitro in the new concept of triggered radiosensitizer delivery, in which cells were only sensitized to radiotherapy treatment after simultaneous treatment of TSLs and hyperthermia and II) in vivo in comparison with un-encapsulated drug, in which TSL in combination with local hyperthermia treatment increased survival, increased intratumoral drug concentrations and caused a more evenly drug distribution in the tumor. Prodrugs are activated by a trigger, like enzymes in enzyme prodrug therapy. The efficacy of enzyme prodrug therapy was improved by I) increasing the amount of enzymes available for prodrug conversion by exposing cells to high-intensity focused ultrasound to liberate these enzymes, II) increasing the conversion rate of the prodrug by altering its molecular structure and III) increasing the circulation time by encapsulating the prodrug into a nanogel formulation. These preclinical results showed effective treatment by TSLs and prodrugs only after physical activation of these local drug delivery strategies.